Inhibition of GluN2B-containing N -methyl- D- aspartate receptors by radiprodil

作者：Tue G. Banke, Michael C. Regan, Riley E. Perszyk, Lu Zhang, Hao Xing, Jiahui Chen, Sehoon Won, Noriko Simorowski, Eva Sarai Diaz, Sukhan Kim, Rui Song, Jian Rong, Xin Zhou, Ahmad Chaudhary, Jing Zhang, John F Traynelis, Ellington D. McDaniels, Karolina Nitsche, Steve Roache, Christopher S. Raymond, Chian‐Ming Low, Scott J. Myers, Katherine W. Roche, Steven H. Liang, Stephen F. Traynelis, Hiro Furukawa, Hongjie Yuan · 发表于：Brain · 年份：2025 · DOI：10.1093/brain/awaf355 · 被引用次数：3 · 研究领域：Neuroscience and Neuropharmacology Research、Epilepsy research and treatment、Chemical Synthesis and Analysis

N-methyl-D-aspartate (NMDA) receptors mediate a slow, Ca2+-permeable component of excitatory synaptic transmission in the brain and participate in neuronal development and synaptic plasticity. Most NMDA receptors are tetrameric assemblies of two GluN1 and two GluN2 subunits encoded by five genes (GRIN1 and GRIN2A-GRIN2D), which produce GluN1 and GluN2A-GluN2D subunits. NMDA receptors that contain the GluN2B subunit have unique pharmacological properties, being inhibited by multiple structurally distinct series of biaryl compounds with high potency and selectivity. These agents are of considerable therapeutic interest, given the numerous roles that GluN2B-containing NMDA receptors play in normal brain function and pathological situations. Among GluN2B-selective negative allosteric modulators, radiprodil inhibits NMDA receptors that contain GluN2B with high potency and selectivity and appears to be safe in humans. Here, we evaluate the structural determinants of radiprodil binding to the heterodimeric GluN1-GluN2B amino terminal domain by X-ray crystallography and explore the molecular mechanism of inhibition. A large number of de novo variants have been identified in the GRIN gene family in patients with various neurological and neuropsychiatric conditions, including autism, intellectual disability, epilepsy, language disorders and movement disorders. We show that radiprodil is an effective antagonist at >80% of human disease-associated GRIN1 and GRIN2B missense variants teste...